Stereoselective Synthesis of 1-Aminocyclopropanecarboxylic Acid Carnosadines via Inter-intramolecular Double Alkylation with Optically Active 2-Methylaziridine Derivatives

Abstract

The stereoselective and short-step synthesis of N-protected allo-carnosadine, ent-carnosadine, and carnosadine lactam was accomplished from a common cyclopropane intermediate. The inter-intramolecular double alkylation of diethyl malonate with an optically active 2-methylaziridine derivative gave the key cyclopropane in excellent yield and optical purity. The following monohydrolysis of the diester moiety using different reaction conditions provided both diastereomers of monoacids, which were converted to three carnosadine derivatives in 5–6 steps from the common diester.

Base-Promoted Intramolecular Addition of Vinyl Cyclopropanecarboxamides to Access Conformationally Restricted Aza[3.1.0]bicycles

“…Occasionally, the same conversion starting from enyne analogues has also been achieved by a photocatalytic pathway [34][35][36] as well as metal-free organocatalytic processes [37][38][39][40][41][42], mechanisms that are similar to the metal carbene processes (Scheme 1a). Another two effective approaches for the synthesis of 3-azabicyclo[3.1.0]hexanes involve the derivatization reactions of substituted cyclopropanes, such as C(sp 3 )-H bond activated alkenylation/amination tandem reactions and intramolecular aminolysis reactions Molecules 2023, 28, 3691 2 of 15 (Scheme 1b) [43][44][45][46][47][48][49][50][51][52][53], and the reaction of functionalized maleimide derivatives with one carbon donor generated in situ derived from substituted diazomethanes, bromo(nitro)methane, substituted α-diazoacetates, and N-tosylhydrazones via an intermolecular [2+1] fusedannulation reaction (Scheme 1c) [54][55][56][57][58][59][60][61][62][63][64]. In particular, the base-induced intramolecular spirocyclization method of the alkylation subunit precursor appeared to be a more efficient proprietary reaction to access 3-azabicyclo[3.1.0]hexane scaffold-containing natural products via aryl metal or radical dearomatization/cyclization reactions (Scheme 1d) [65][66][67][68][69][70][71]…”